Temporomandibular joint disorders (TMJDs) are painful, progressive, chronic disorders that affect more than 10 million people of all ages in the US population. The management of TMJDs and associated pain is a challenge. Due to the multifaceted nature of the TMJ complex, etiologies of TMJDs are heterogeneous but commonly result from trauma and/or inflammation. It is widely accepted that mechanical forces play a key role in pathogenesis, as well as the repair of TMJ articular surfaces. It is puzzling how signals generated by mechanical forces in some instances initiate inflammation and pathologies, and how in other instances these signals are therapeutic. It is our hypothesis that, "Fibrochondrocytic responses to mechanical forces are magnitude dependent and regulate proinflammatory and anti-inflammatory pathways to initiate cartilage destruction or repair." The rationale for this hypothesis is based on our recent observations that, signals generated by cyclic tensile strain of high magnitude (CTS-H) upregulate proinflammatory gene induction, in vitro. On the other hand, CTS of low magnitude (CTS-L) markedly suppresses TNF-alpha- and IL-1beta-dependent mRNA transcription of multiple proinflammatory genes involved in cartilage destruction. Our long term goals are to elucidate the cellular and molecular events that lead to remodeling of the fibrocartilage of TMJ during adaptation to normal and pathological loading. Specifically, we will identify molecular mechanisms of the magnitude-dependent effects of mechanical signals [tensile (CTS) and compressive (CCF)] in the etiology, pathophysiology, and functionally adaptive phases of TMJDs by determining: (i) How various magnitudes of CTS or CCF exert proinflammatory or anti-inflammatory/reparative effects on TMJ fibrochondrocytes; (ii) The optimal time and frequency of CTS and CCF required for its proinflammatory and sustained anti-inflammatory/reparative effects on fibrochondrocytes in the absence or presence of rhTNF-alpha and rhlL-1beta; (iii) The target sites of CTS and CCF on NFKappaB pathway in the absence or presence of rhTNF-alpha or rhlL-1beta; and (iv) The target sites of CTS and CCF on the activator protein-1 (AP-1) pathway in the absence or presence of rhTNF-alpha and rhlL-1beta. The results of the proposed studies will be a significant step towards the basic understanding of the pathways involved in mechanical signaling of TMJ cells. Once understood, these pathways can be exploited for the development of physiotherapeutic interventions to limit or reverse the pathology associated with TMJDs.